Chronic pain (CP) affects up to 100 million individuals in the U.S. alone. Management of CP has increasingly relied upon high-dose chronic opioid therapy, with this change paralleled by increasing numbers of individuals affected by opioid abuse, and dramatic rises in opioid-related overdose and death. While providing effective pain relief for many, approaches proven to reduce reliance upon high-dose chronic opioids are sorely needed. We have recently identified links between endogenous opioid (EO) function and responses to opioid analgesic medications. Our findings are consistent with an Opioid Supplement Model, in which opioid analgesic medications may serve to supplement natural EO levels to maximize opioid receptor-related pain inhibition. This model has important clinical implications, as it suggests that desired levels of pain relief might be achieved not by high-dose opioid analgesics alone, but rather by a combination of nonpharmacological strategies that enhance EO function with lower dosages of opioid analgesics, potentially mitigating side effects and risks associated with opioid analgesics. This project seeks for the first time to directly test the Opioid Supplement Model in 116 individuals with chronic low back pain. Specific aims are: 1) determine whether an aerobic exercise manipulation reduces evoked and chronic pain responsiveness via enhanced EO function, 2) determine whether this exercise manipulation permits achieving targeted levels of pain relief at lower opioid analgesic dosages through its effects on enhanced EO function, and 3) whether changes in Aim 2 are associated with reduced side effects and abuse-relevant drug effects (drug liking, high, euphoria, etc.). This project will incorporate a unique combination of expertise and methodologies to achieve these aims, including a randomized, controlled 6 week aerobic exercise training manipulation, assessment of pre- to post- manipulation changes in daily chronic back pain intensity based on electronic diaries, and controlled laboratory assessment of pre- to post-manipulation changes in EO function (indexed by effects of opioid blockade on evoked pain responses relative to placebo condition) and opioid analgesic responsiveness (to a series of incremental morphine doses). If hypotheses are confirmed, results could substantially alter CP management by facilitating mechanism-based strategic combinations of nonpharmacological and pharmacological pain therapies to achieve acceptable pain relief with fewer side effects and reduced abuse risk. Findings would also add important knowledge to the sparse human literature regarding links between CP, EO function, and responses to opioid analgesics, knowledge with important implications for achieving the goal of personalized pain medicine. Project results would potentially lead to changes in clinical practice with significant population level benefits, given he frequency with which chronic high-dose opioids are currently used and their increasingly recognized negative sequelae.